As the rates of obesity continue to rise, the need to understand its pathogenesis grows ever more pressing. The hormone, leptin, signals via the long isoform of its receptor(LepR-b) in the central nervous system to regulate diverse determinants of energy balance, including food intake, energy expenditure, and neuroendocrine output. The specific neuronal populations by which leptin modulates each of these functions remain largely undetermined, however. Identifying the crucial neuronal population(s) that mediate the regulation of energy balance by leptin is essential for the development of appropriately targeted anti-obesity therapies. LepR-b expression in the brain is distributed among a number of areas, primarily within the hypothalamus and brainstem. Although the hypothalamic arcuate nucleus (ARC) is important for energy balance and plays a role in leptin action, the key site for leptin action on energy balance has yet to be identified, and many sets of LepR-b neurons remain poorly understood - including those in the dorsomedial hypothalamus (DMH). The DMH contains a large population of LepR-b neurons and this nucleus is densely connected to the ARC and paraventricular nucleus (PVH), which are crucial for the control of feeding and overall energy balance. The goal of this research proposal is to understand the neurobiology of DMH LepR-b neurons, as well as their role in controlling parameters of energy balance and metabolism. We will use a molecular genetic techniques combined with stereotaxic injection of cell-specific viral systems to define neurons afferent and efferent to DMH LepR-b neurons and thus to understand the circuits in which these neurons function. We will also use molecular techniques in combination with stereotaxic injection to manipulate the physiology of DMH LepR-b neurons, in order to study their function. Altogether these studies will elucidate neuronal mechanisms through which leptin regulates energy balance, and will bolster our understanding of leptin action in the DMH. At the completion of these studies we hope to gain critical insight into the mechanisms of leptin action in the central nervous system. PUBLIC HEALTH RELEVANCE: Obesity contributes to the development of atherosclerosis and diabetes. By elucidating the role of leptin receptor neurons in the dorsomedial hypothalamic nucleus in the control of body weight, we will identify processes that may be important for the pathophysiology of obesity